June 13, 2015 12:15 am / Leave a comment
As research laboratories across the world investigate new lupus treatments, efforts increasingly focus on suppressing B-cell activity. B-cells are major actors in the normal immune response. With lupus, the immune response is not normal and neither is the behavior of B-Cells. During an active disease phase, the immune system attacks organs and wreaks havoc. B-cells play an important role in this process.
Historically, lupus medicines have sought to control the aberrant immune response by tamping down the entire immune system. Established remedies (for example: glucocorticoids and cyclophosphamide) are not very specific in suppressing the immune system. Instead of acting on the parts of the system that are especially aggressive, older medicines depress the general immune response. While this approach is often effective in controlling symptoms, it can sometimes have a devastating impact on the overall health of the patient.
An analogy to the traditional approach might be found in the case of a broken light switch. In order to repair the switch, an electrician could shut down all the circuits in a house. This certainly would insure that electricity isn’t flowing to the broken switch–it would also insure that electricity isn’t flowing anywhere else in the house, either. A total shutdown might have far-reaching consequences–melting ice cream, for instance. However, if the electrician decided to shut off only the circuit associated with the broken switch–that is, if she/he targeted the problem area–disruption in the household would be minimized.
That’s the principle behind targeted B-cell suppression. If only B-cells are affected, the impact on the patient might not be as widespread as it would be if an older generation, immune-suppressant drugs were administered.
The problem with new generation, B-cell-targeting drugs is that, so far, they haven’t proven to be very effective. This is the case with belumimab and rituximab. While both of these drugs are prescribed at present and do help people in certain situations, neither has lived up to its early promise.
Epratuzumab is a B-cell-targeting drug with a difference. This drug doesn’t try to suppress all B-cell activity. It is designed to address only a specific part of the B-cell: CD-22, which is on the surface of the cell.
It is believed that a major benefit of epratuzumab over other B-cell-targeting drugs may be that it does not depopulate all of the B-cells in the course of treatment. It seems that epratuzumab only eliminates “up to 45% of circulating B-cells“. Rituximab, on the other hand, eliminates greater than 90% of circulating B-cells. Since B-cells are essential for a robust immune response, wiping these cells out increases the risk of infection. Keeping viable B-cells might help to limit that risk.
Epratuzumab has gone through Phases I and Phase II clinical trials. Phase III is currently underway. A January 2013 article published in the Annals of Rheumatology describes the drug as promising. The journal reports that epratuzumab was well tolerated by study participants, even at high doses (2400 mg. week); also, the journal reports, trial subjects who received the medication experienced better outcomes than the control group that received placebo.
In February 2015 Euroscan (a European evaluating organization) issued a report on the safety of epratuzumab and side effects experienced by study subjects. Side effects were noted to have occurred as follows: 10% experienced conjunctivitis; 45% upper respiratory infections; 28% diarrhea and 28% headache; 14% experienced migraine and 34% caught a cold; 24% experienced nausea; 24% had bronchitis; dizziness was reported by 10%; 10% ran a fever; sinusitis was reported in 31%; abdominal pain occurred in 31%; 10% had chest pain; 10 % had a cough.
Phase III of the epratuzumab clinical trial has 1400 participants; these patients have moderate to severe SLE. The final report on Phase III will be issued in 2019. The drug’s manufacturer, UCB and Immunomedics is optimistic, based on the results of Phase I and Phase II. UCB reports that study participants who received epratuzumab showed a “24.9% treatment advantage over placebo”.
Will epratuzumab be a ‘magic bullet’ for lupus patients? A lot of people certainly hope so. Clinical trials and actual practice will prove whether or not this hope is misplaced.
June 9, 2015 12:44 am / Leave a comment
In September of 2012 I posted a blog about a biologic, Rituximab. Some researchers had hoped this medication would prove to be an effective treatment for SLE. Unfortunately, Rituximab did not live up to expectations. However, the drug has been used to treat SLE in rescue situations. As such, it is tried when other options have failed. In many of these cases, Rituximab has been effective, especially when used along with other drugs.
Even though clinical trials of Rituximab have not yielded promising results, investigation continues to see if it might be useful as part of a regimen with other lupus treatments. As experience with Rituximab accumulates–in doctors’ practices and in trials–data is collected about potential side effects. It is important for physicians and patients to be alert to these so that prompt action may be taken, if necessary.
A 2015 Hindawi Journal article reports a case of early-onset neutropenia and thrombocytopenia that was associated with the administration of Rituximab. The patient’s treating physicians entertained the possibility that these conditions may not have been caused by Rituximab but may have been a manifestation of SLE. This analysis was rejected because the patient’s clinical profile did not support the conclusion.
This case of early-onset neutropenia and thrombocytopenia associated with Rituximab is unusual, if not unique. The authors of the Hindawi article contemplate the possibility that the side effects may have also occurred in other cases but were not detected.
In any event, both neutropenia and thrombocytopenia were transient in this case. The conditions cleared up 12 days after Rituximab therapy stopped.
One thing that should be remembered as side effects of Rituximab are discussed: the medicine is used for very sick people, people who may not have many other options. Side effects will likely not be a reason to avoid treatment, but being aware of those side effects may help to keep the patient safe while treatment proceeds.